Biological pacemaker induced by focal cardiac transduction with AAV-TBX18.
Publication Year:
2026
PubMed ID:
41108077
Funding Grants:
Public Summary:
Scientists have been trying to create "biological pacemakers" by injecting a specific gene into the heart, but the body's immune system usually destroys these newly modified cells too quickly. To solve this, researchers recently tested a gentler delivery method using a modified virus that sneaks past the body's defenses without triggering heavy inflammation. When they injected this newly packaged gene into the hearts of rats and pigs suffering from dangerously slow heartbeats, it successfully reprogrammed regular heart muscle into specialized, self-beating pacemaker cells. These new biological pacemakers not only kept the animals' hearts beating at a healthy, steady rate for over a month, but they also naturally adjusted to the body's needs, safely speeding up the heart rate during physical exercise. Ultimately, this breakthrough proves that using a stealthier gene-delivery system could one day provide patients with a long-lasting, natural alternative to traditional electronic pacemakers.
Scientific Abstract:
When injected into the heart, adenovirally packaged T-box transcription factor 18 (TBX18) induces biological pacemaker activity, but immunological clearance of transduced cells limits efficacy. Here, we investigated whether expressing TBX18 in the less inflammatory adeno-associated virus (AAV-TBX18) represents a viable alternative. Focal injection of AAV-TBX18 (but not a control AAV expressing green fluorescent protein [AAV-GFP]) in the left ventricle of rats altered local gene expression to resemble that of the sinoatrial node and unleashed automaticity originating at the site of injection. AAV-TBX18-induced pacemakers exhibited autonomic responsiveness, while increasing maximal exercise tolerance. Likewise, catheter-based delivery of AAV-TBX18 (but not AAV-GFP) into the His bundle region in pigs increased heart rate in a clinically relevant porcine model of complete atrioventricular block. The heart rate remained significantly higher in AAV-TBX18 animals than in AAV-GFP controls for at least 6 weeks in rats and 4 weeks in pigs. Thus, targeted intramyocardial injection of AAV-TBX18 induces durable, physiologically responsive chronotropic support in both rats and pigs with complete heart block.